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Description : Antiprotozoal Drugs. Malaria is the most important parasitic disease of humans • Four species of plasmodium typically cause human malaria: • Plasmodium falciparum (Major complications), • P vivax, • P malariae, and • P ovale. • P knowlesi (mainly affects monkeys) • Drug resistance is an important therapeutic problem, most notably with P falciparum

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Published on : Nov 06, 2020 | Views : 4305 | Downloads : 32

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Antiprotozoal Drugs (Drugs for Malaria, Trypanosomiasis, Leishmaniasis and Others protozoa Infections) Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology
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Malaria Plasmodium falciparum
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Malaria Most important parasitic disease of humans • Four species of plasmodium typically cause human malaria: • Plasmodium falciparum (Major complications), • P vivax, • P malariae, and • P ovale. • P knowlesi (mainly affects monkeys) • Drug resistance is an important therapeutic problem, most notably with P falciparum
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Life cycle of Parasites Sporozoites (asexual form of the parasite) are introduced into the host following insect bite and these develop in the liver into: • schizonts (the pre-erythrocytic stage), • which liberate merozoites, which infect red blood cells, forming motile trophozoites, which, after development, release another batch of erythrocyte-infecting merozoites, causing fever; this constitutes the erythrocytic cycle dormant hypnozoites, which may liberate merozoites later (the exoerythrocytic stage) Some merozoites develop into gametocytes, the sexual forms of the parasite. When ingested by the mosquito, these give rise to further stages of the parasite’s life cycle within the insect
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Drug Classification • Drugs that eliminate developing or dormant liver forms are called tissue schizonticides • Those that act on erythrocytic parasites are blood schizonticides; • Those that kill sexual stages and prevent transmission to mosquitoes are gametocides • No single available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages • Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection. • However, chemoprophylactic agents kill erythrocytic parasites before they increase sufficiently in number to cause clinical disease
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Site of action of antimalarial drugs
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MOA of antimalarial drugs
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1. Chloroquine MOA • The drug probably acts by concentrating in parasite food vacuoles, • Preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, and Thus eliciting parasite toxicity due to the buildup of free heme • Resistance - mutations in a putative transporter, PfCRT • Resistance can be reversed by verapamil, desipramine, and chlorpheniramine (not clinically proven) • Used for Treatment & Chemoprophylaxis • Uncomplicated nonfalciparum and sensitive falciparum – Treatment • Chemoprophylaxis malarious regions - without resistant falciparum malaria • Amebic liver abscess (failure therapy with metronidazole) . Rheumatoid Arthritis
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1. Chloroquine Adverse effects • Hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient • Impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes. • Irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy (long-term) • IM injections or IV infusions cause severe hypotension and respiratory and cardiac arrest, and should be avoided. • Pruritus, anorexia, malaise, blurring of vision, and urticaria (uncommon) • Dosing after meals may reduce ADRs
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1. Chloroquine Contraindications • Psoriasis or porphyria • Retinal or visual field abnormalities • Myopathy • Patients with liver, neurologic, or hematologic disorders • Kaolin and calcium- and magnesium-containing antacids interfere with the absorption of chloroquine • Other Quinolones: Piperaquine; Amodiaquine
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2. Artemisinin & its derivatives MOA Blood schizonticides against all human malaria parasites • Artesunate (water soluble; oral, intravenous, intramuscular, and rectal administration) • Artemether (lipid-soluble; oral, intramuscular, and rectal administration) • Dihydroartemisinin (water-soluble; oral administration) • Monotherapy is discouraged • Uncomplicated falciparum malaria –First-line standard therapy
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2. Artemisinin & its derivatives Result from the production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge • No effect on hepatic stages • They are active against young, but not mature gametocytes • Adverse effects • Hemolysis (delayed) – more common (13%) • Neutropenia, anemia, elevated liver enzymes, and allergic reactions • Embryotoxic in animal studies?
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3. Quinine & Quinidine Quinine is derived from the bark of the cinchona tree, a traditional remedy • Quinine is a rapid-acting, highly effective blood schizonticide against 4 species • Gametocidal against P vivax and P ovale • Clinical Applications • Parenteral treatment of severe falciparum malaria • Administered slowly with cardiac monitoring due to cardiac toxicity (IV infusion/ divided by doses/ loading dose) • Oral treatment of falciparum malaria -Quinine sulfate for uncomplicated falciparum • Malarial chemoprophylaxis • Babesiosis (Babesia Microti)
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3. Quinine & Quinidine Adverse Effects • Cinchonism • tinnitus, headache, nausea, dizziness, flushing, and visual disturbances • visual and auditory abnormalities (Prolonged therapy) • Hypersensitivity reactions (skin rashes, urticaria, angioedema, and bronchospasm). • Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria • Hematologic abnormalities include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia • Hypoglycemia (increase insulin release) -problem in severe infections and in pregnant patients • Thrombophlebitis (IV route) • Severe hypotension • Electrocardiographic abnormalities (QT interval prolongation) – Common with IV administration, dangerous arrhythmias
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3. Quinine & Quinidine Contraindications & Cautions • Discontinued if signs of severe cinchonism, hemolysis, or hypersensitivity • Visual or auditory Problems • Cardiac abnormalities • Quinine should not be given concurrently with mefloquine • Quinine can raise plasma levels of warfarin and digoxin. /patients recently received mefloquine • Dosage must be reduced in renal insufficiency • Aluminum-containing antacids (reduce absorption)
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4. Mefloquine Recommended for chloroquine-resistant strains • Long half-life 20 days, allowing weekly dosing for chemoprophylaxis • Blood schizonticidal activity against P falciparum and P vivax • Chemoprophylaxis & Treatment • Artesunate-mefloquine is the first-line therapy for uncomplicated falciparum • Adverse Effects • Neuropsychiatric toxicities (depression, confusion seizures and psychosis) – 50 % • Contraindications • History of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects
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5. Primaquine Choice for the eradication of dormant liver forms of P vivax and P ovale • Gametocidal agent • Clinical Applications: • Therapy (radical cure) of acute vivax and ovale malaria • Terminal prophylaxis of vivax and ovale malaria (diminish the likelihood of relapse) • Pneumocystis jiroveci infection (Clindamycin and Primaquine) • Adverse Effects • Hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects • Leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. • Contraindications & Cautions • Prior testing of G6PD deficiency is recommended • History of granulocytopenia or methemoglobinemia, with myelosuppressive drugs • Discontinue if any evidence of hemolysis or anemia
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6. Atovaquone Recommended for the treatment and prevention of malaria • Acts against plasmodia by disrupting mitochondrial electron transport • Active against tissue and erythrocytic schizonts • Mild to moderate Pneumocystis jiroveci infection (Clindamycin and Primaquine) • Toxoplasmosis in immunocompromised patients (unresponsive to other agents) • Reversible elevations in liver enzymes (ADRs)
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7. Inhibitors of Folate synthesis • Pyrimethamine & Proguanil • Fansidar, a fixed combination of the sulfonamide Sulfadoxine+Pyrimethamine • MOA • Pyrimethamine and proguanil inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. • Sulfonamides inhibit another enzyme, dihydropteroate synthase • Resistance : mutations in dihydrofolate reductase and dihydropteroate synthase • Clinical Uses • Chemoprophylaxis (not as monotherapy), • Intermittent preventive therapy (new strategy for malarial control) • Treatment of chloroquine-resistant falciparum malaria • Toxoplasmosis & Pneumocystosis by P jiroveci • Adverse effects • Severe cutaneous allergic reactions • Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis • They should be used cautiously in the presence of renal or hepatic dysfunction
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8. Antibiotics • Tetracycline and doxycycline are active against erythrocytic schizonts • Doxycycline is used in the treatment of falciparum malaria in conjunction with quinine • Clindamycin is slowly active against erythrocytic schizonts • Azithromycin and fluoroquinolones – Suboptimal efficacy 9. Other antimalarial agents: • Halofantrine, lumefantrine, & Pyronaridine • Alters cardiac conduction, with dose-related prolongation of QT and PR intervals (Halofantrine)
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Amebiasis Endameba histolytica
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Drugs for Amebiasis Entamoeba histolytica. • This organism can cause asymptomatic intestinal infection, • Mild to moderate colitis, • Severe intestinal infection (dysentery), • Ameboma, • Liver abscess, and other extra intestinal infections • Treatment of Specific Forms of Amebiasis • Asymptomatic intestinal infection • Amebic Colitis • Extra intestinal Infections
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Metronidazole & Tinidazole Treatment of extraluminal amebiasis • It kills trophozoites but not cysts of E histolytica • Clinical uses: Amebiasis, Giardiasis, Trichomoniasis • Adverse Effects & Cautions • Dry mouth, and a metallic taste in the mouth • Metronidazole has a disulfiram-like effect • Caution in patients with CNS disease - seizures or peripheral neuropathy (IV infusion) • Potentiate the anticoagulant effect of coumarin-type anticoagulants • It increases lithium toxicity • Other anti-amebic drugs: • Iodoquinol, diloxanide furoate, paromomycin sulfate - Luminal amebicides • Emetine & dehydroemetine - Against tissue trophozoites of E histolytica,
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African Trypanosomiasis & Leishmaniasis Leishmania donovani Trypanosoma brucei
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Pentamidine • Only administered parenterally for pulmonary and extrapulmonary disease caused by P jiroveci • Pneumocystosis - (Inhaled as a nebulized powder for the prevention) • Primary or secondary prophylaxis against pneumocystosis in immunocompromised individuals (with advanced AIDS) • African Trypanosomiasis (Sleeping sickness) – T. brucei gambiense with CNS involvement • Leishmaniasis - Treatment of visceral Leishmaniasis • Adverse Effects & Cautions • Severe hypotension, tachycardia, dizziness, and dyspnea (Rapid IV administration) • Drug should be administered slowly & Patients monitored closely during treatment • Pancreatic toxicity is common. • Hypoglycemia due to inappropriate insulin release
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Other antiprotozoal drugs Antimonials • Meglumine antimoniate & Sodium stibogluconate • Indicated for cutaneous and visceral leishmaniasis • T-wave changes and QT prolongation (ADRs), monitor ECG • Nitazoxanide • Used against Giardia lamblia and Cryptosporidium parvum • Suramin • First-line therapy for early hemolymphatic East African trypanosomiasis • Melarsoprol • First-line therapy for advanced CNS East African trypanosomiasis, and second-line therapy for advanced West African trypanosomiasis • A reactive encephalopathy (ADRs – need corticosteroids administration for the treatment)
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Other antiprotozoal drugs • Eflornithine: • An inhibitor of ornithine decarboxylase • First-line drug for advanced West African trypanosomiasis • Benznidazole • Treatment of American trypanosomiasis (Chagas disease) • Nifurtimox • Standard drug for Chagas disease • Amphotericin (Antifungal drug) • Alternative therapy for visceral leishmaniasis • Miltefosine • First effective oral drug for visceral leishmaniasis, may cause teratogenic adverse effects • Paromomycin (aminoglycoside antibiotic) • Treatment of visceral leishmaniasis
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THANK YOU FOR YOUR ATTENTION